Abstract
The Cannabis sativa plant, for its analgesic, anti-inflammatory, antiemetic, and anticonvulsant properties, has been used for thousands of years in Chinese, Indian, and Greek cultures and was introduced into Western medicine in the 19th century. There has been a rise in interest in cannabinoids since the main substances of cannabis were identified, as well as the recognition that the endocannabinoid system (ECS) controls multiple processes in pain treatment and neurologic and mental illnesses. However, the ECS has also been associated with negative effects, including harmful effects on emotional and cognitive functions, the development of tolerance and dependence, and withdrawal symptoms after drug cessation in humans. We recently found that repeated intraperitoneal administration of the two main components of cannabis, delta-9-tetrahydrocannabinol (THC) and cannabinolic acid (CBNA), led to the development of tolerance in male mice. In this review, we focus on the evidence demonstrating cannabinoid tolerance in animals. The common mechanisms and main signaling pathways for cannabinoid tolerance, including neuroadaptations primarily at cannabinoid 1 (CB1) receptors, such as desensitization and downregulation, which are mediated by several signaling pathways, are discussed.
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